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OtherCELLULAR AND MOLECULAR PHARMACOLOGY

The Interactions of Hexachlorocyclohexane Isomers with Human γ-Aminobutyric AcidA Receptors Expressed inXenopus Oocytes

L. S. Aspinwall, I. Bermudez, L. A. King and K. A. Wafford
Journal of Pharmacology and Experimental Therapeutics September 1997, 282 (3) 1557-1564;
L. S. Aspinwall
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I. Bermudez
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L. A. King
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K. A. Wafford
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Abstract

The effects of γ-hexachlorocyclohexane (γ-HCH) and its α, β and δ isomers on the γ-aminobutyric acid (GABA) responses of human α1β3γ2S and α6β3γ2S GABAA receptors expressed in Xenopus oocytes were examined by conventional two-electrode voltage-clamp techniques. γ-HCH induced partial inhibition of EC50 GABA responses, whereas the α and δ isomers produced potentiation of EC20GABA currents. In contrast, β-HCH had no effect on GABA currents, even at concentrations as high as 100 μM. The effects of the active HCH isomers were not influenced by alpha subunit composition because there was no significant difference in either the inhibition or potentiation of α1β3γ2S or α6β3γ2S GABAA receptors. δ- and γ-HCH antagonized picrotoxin inhibition and caused displacement of specific [35S]t-butylbicyclophosphorothionate binding. δ-HCH potentiation was found to be additive with steroid, loreclezole and lanthanum potentiation, but nonadditive with potentiation by pentobarbital and propofol, which suggested that its activity was linked to the barbiturate site.

Footnotes

  • Send reprint requests to: Dr Keith A Wafford, Merck Sharp & Dohme Research Labs, Terlings Park, Eastwick Road, Harlow, Essex CM20 2QR United Kingdom.

  • ↵1 Supported by a CASE BBSRC PhD studentship with Merck Sharp & Dohme, U.K.

  • Abbreviations:
    GABA
    γ-aminobutyric acid
    MBS
    modified Barth’s solution
    HCH
    hexachlorocyclohexane
    TBPS
    t-butylbicyclophosphorothionate
    5α
    3α-DHP, 5α-pregnan-3α-ol-20-one
    HEPES
    4-(2-hydroxyethyl)-1-piperazineethanesulfonic acid
    • Received February 25, 1997.
    • Accepted May 5, 1997.
  • The American Society for Pharmacology and Experimental Therapeutics
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Journal of Pharmacology and Experimental Therapeutics
Vol. 282, Issue 3
1 Sep 1997
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OtherCELLULAR AND MOLECULAR PHARMACOLOGY

The Interactions of Hexachlorocyclohexane Isomers with Human γ-Aminobutyric AcidA Receptors Expressed inXenopus Oocytes

L. S. Aspinwall, I. Bermudez, L. A. King and K. A. Wafford
Journal of Pharmacology and Experimental Therapeutics September 1, 1997, 282 (3) 1557-1564;

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OtherCELLULAR AND MOLECULAR PHARMACOLOGY

The Interactions of Hexachlorocyclohexane Isomers with Human γ-Aminobutyric AcidA Receptors Expressed inXenopus Oocytes

L. S. Aspinwall, I. Bermudez, L. A. King and K. A. Wafford
Journal of Pharmacology and Experimental Therapeutics September 1, 1997, 282 (3) 1557-1564;
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  • Inhibition of Voltage-Dependent Sodium Channels by the Anticonvulsant γ-Aminobutyric Acid Type A Receptor Modulator, 3-Benzyl-3-Ethyl-2-Piperidinone
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